Abstract

Diminished immunity in aged individuals has in part been attributed CD8 T cell senescence due to repeated antigen exposure and proliferation. Senescent-like CD8 T cells defined as CD27–CD28–CD8+ have been associated with impaired T cell receptor (TCR) signaling, proliferation, and growth. Pereira et al. hypothesize that senescent-like T cells develop mechanisms of activation distinct from conventional TCR signaling and proliferation, which maintain protective immunity in aged individuals. Two previous findings suggested a potential mechanism: the up-regulation of receptors associated with natural killer (NK) cell cytotoxicity in immunosenescent CD8+ and the mediation of TCR signaling impairment by stress-sensing sestrins in CD4+ T cells. The authors addressed whether NK receptors and sestrins modulate the function of senescent-like CD8 T cells using both in vitro human and in vivo mouse studies. They first established the effect of NK receptors on T cell function. As naïve CD8+ T cells differentiate into CD27–CD28– effectors, they gain expression of cytotoxic genes, NK receptors and the adapter protein DAP12 resulting in enhanced NK-like cytotoxicity in senescent-like CD8+ T cells. Additionally, in highly differentiated effector T cells, levels of sestrin 2 and phosphorylated JNK were elevated and these proteins were shown to colocalize with NKG2D and DAP12. Loss of JNK or sestrins in aged mice augmented immune function and inflammation evidenced by improved delayed-type hypersensitivity. However, tumor killing in aged mice was impaired in the absence of sestrins. Analysis of responses to yellow fever vaccination indicate that sestrin-mediated up-regulation of NKG2D is not limited to aging, but also can occur in effectors after exposure to antigen. Taken together, sestrins induce an NK-like program in aged effector CD8+ T cells with impaired TCR signaling and proliferation, but enhanced cytotoxicity mediated through NKG2D. This may be a mechanism that compensates for the defects associated with long-term stimulation of T cells that can occur with aging and in response to latent viral infection. Because NKG2D signaling is antigen-independent, it is not limited by the breadth or specificity of the TCR repertoire. These findings suggest that temporary sestrin blockade could improve vaccination strategies and enhance antigen-specific T cell responses to viral infection in aged populations.